According to the American Heart Association, atherosclerosis, partly because of high cholesterol (hypercholesterolemia) and triglyceride (hypertriglyceridemia), is the leading cause of cardiovascular diseases. Although statins (HMG CoA reductase inhibitors) significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease, they have been shown to cause liver damage in some people, particularly those needing high doses or combination therapy. Only 38% of these patients achieved the low-density lipoprotein cholesterol goals set by the National Cholesterol Education Program and more aggressive treatment of dyslipidemia is needed. Among the patients in need of alternatives to statin therapies are those who cannot tolerate statins, are resistant to statins and those with familial hypercholesterolemia. In familial hypercholesterolemia patients, where 1 in every 500 children is born with abnormal lipid profiles that predispose them to premature arteriosclerosis, a potent lipid lowering or combinations of agents might be required.
Thyroid hormones affect most mammalian tissues. In excess, these hormones may cause weight loss, tachycardia, atrial arrhythmias, and heart failure. Further physiological responses are reduction of plasma cholesterol levels, elevated mood, and muscle wasting (Utiger R D (1995): The thyroid: physiology, thyrotoxicosis, hypothyroidism, and the painful thyroid, In: Felig P F, Baxter J D, Frohman C A (eds) Endocrinology and Metabolism, MacGraw-Hill, New York, pp 435-519). Some effects of thyroid hormones could be beneficial; e.g. lowering plasma cholesterol levels or inducing weight loss in obese individuals. Other effects, such as promotion of tachycardia and subsequent heart failure, are deleterious and can outweigh beneficial properties of thyroid hormone analogs (von Olshausen K, Bischoff S, Kahaly G, Mohr-Kahaly S, Erbel R, Beyer J, Meyer J (1989): Cardiac arrhythmias and heart rate in hyperthyroidism, Am J Cardiol 63:930-933). If hormone analogs could be made to be selective in their effects, adverse actions of thyroid hormone might be avoided. The thyroid receptor beta1 (TRβ1) and thyroid receptor beta2 (TRβ2) isoforms differ in their amino termini, but both bind and respond to thyroid hormone. Selective modulation of thyroid receptor (TR) action might be useful in treating obesity and hypercholesterolemia and other lipid disorders. GC-1 and KB-2115 has been shown to lower serum cholesterol and triglyceride, risk factors for atherosclerosis (Trost S U, Swanson E, Gloss B, Wang-Iverson D B, Zhang H, Volodarsky T, Grover G J, Baxter J D, Chiellini G, Scanlan T S, Dillmann W H (2000): The thyroid hormone receptor-β-selective agonist GC-1 differentially affects plasma lipids and cardiac activity, Endocrinology 141:3057-3064; Berkenstam A, Kristensen J, Mellstrom K, Carlsson B, Malm J, Rehnmark S, Garg N, Andersson C, Rudling M, Sjoberg F, Angelin B, Baxter J (2008): The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans, Proc. Natl. Acad. Sci. USA 105, 663-667; Scanlan T (2010): Sobetirome: a case history of bench-to-clinic drug discovery and development, Heart Fail. Rev. 15, 177-182).
Pharmacological approaches to selectively stimulate TRβ1 activity are based on the development of compounds that interact with the C-terminal LBD and modulates receptor activity. KB2115 (eprotirome) is another TRβ1 selective compound that has been tested in humans (Berkenstam A, Kristensen J, Mellstrom K, Carlsson B, Malm J, Rehnmark S, Garg N, Andersson C, Rudling M, Sjoberg F, Angelin B, Baxter J (2008): The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans, Proc. Natl. Acad. Sci. USA 105, 663-667). Eprotirome was administrated to moderately overweight and hypercholesterolemic subjects for two weeks. Serum total and LDL cholesterol as well as apoB levels were reduced without detectable effects on the heart (Taylor A, Stephan Z, Steele R, Wong N (1997): Beneficial effects of a novel thyromimetic on lipoprotein metabolism, Mol. Pharmacol. 52, 542-547). Bile acid synthesis serves as the major elimination route of excess cholesterol indicating that eprotirome induced net cholesterol efflux. Eprotirome has also been tested in combination with either ezetimibe or statin therapy in hyper-cholesterolemic patients. GC-1 was shown to be effective in lowering serum cholesterol and triglyceride in Phase I clinical trial. However, a recent animal toxicology study demonstrated unwanted effects following mid to long-term exposure halting the advancement of the whole TR beta1 agonist class. Cartilage damage was observed in dogs given eprotirome for up to 12 months. This cartilage damage occurred in all animals treated with high doses but was also seen in the lower dose groups, while control animals displayed no damage. Unfortunately, this undesirable side effect has jeopardized the use of thyromimetic as a general therapy for hypercholesterolemia and other lipid disorders.